Obesity has reached pandemic proportions. Currently, the only effective long term treatment for severe obesity is bariatric surgery. However, the mechanisms of reduced food intake and weight loss after obesity surgery, particularly Rouen-Y gastric bypass (RYGB), are not well understood. This study utilizes functional magnetic resonance imaging (fMRI) and measures of appetite-related gut peptide levels pre and post bariatric surgery to investigate the neurological and hormonal mechanisms involved in initiation and termination of meals. Participants will be studied prior to surgery, 3 mo post surgery (during rapid weight loss), and 18 mo post surgery (when weight loss has generally stabilized).Two surgical groups, laparoscopic RYGB and gastric banding (GB), will be compared to two control groups: i) participants losing weight on a 3-mo formula diet (WL), and ii) those who qualify for, but choose not to undergo surgery and receive no treatment (NT). fMRI will be used to examine areas of brain activation in response to visual and auditory stimuli of high- palatability foods (HPF), low-palatability foods (LPF), and non-foods (NF) following a fixed meal. From pre to post RYGB, in response to HPF stimuli, we anticipate the greatest reduction in key brain areas associated with food and reward (such as the orbitofrontal cortex [OFC]), a lesser reduction in activation after GB, an increase in WL, and no change in NT. Both surgical operations restrict the size of the stomach but, unlike GB, RYGB involves sectioning the stomach and bypassing a segment of the intestine. This sectioning of the stomach may reduce levels of the orexigenic hormone ghrelin, produced by the stomach, which is involved in meal initiation. In addition, the intestinal bypass may elevate postprandial levels of the anorexigenic hormones, PYY and GLP-1, which are involved in meal termination. These appetite-related hormones will be measured prior to, through, and 1 hour after, a morning fixed liquid meal just before the fMRI. After RYGB, the postprandial gut peptides, all of which cross the blood-brain barrier, should contribute further to reducing brain activation in key reward areas in response to HPF stimuli. We anticipate a decrease in ghrelin, but elevated PYY and GLP-1, following RYGB. The GB group and, to a greater extent, the WL group are expected to experience gut peptide changes opposite in direction to those seen following RYGB. As a secondary aim, we will assess binge eating behavior, which is expected to diminish the most after RYGB. Altogether, we will enroll 136 relatively healthy (non-diabetic) severely obese (BMI = 40-50 kg/m2) men and women, with 34 participants in each of the four groups. The BMI range will ensure that virtually all participants will fit into the fMRI scanner. All four groups will be matched for gender, BMI, and BED status. The findings from the study should improve our knowledge of the biological mechanisms that contribute to appetite and weight reduction after bariatric surgery. This knowledge may lead to non-surgical alternatives that mimic the effects of RYGB on neurological and hormonal changes that result in long-term weight loss. PUBLIC HEALTH RELEVANCE: Obesity has become a world-wide epidemic, and at the same time the number of bariatric surgeries for severely obese people has increased dramatically. The objective of this study is to better understand the mechanisms by which obesity surgery causes weight loss. Changes in brain responses to food stimuli as well as changes in appetite hormones produced by the digestive system will be assessed following two types of obesity surgery: 1) gastric bypass and 2) gastric banding. These two surgical groups will be compared to two non-surgical control groups. The study findings may better explain why surgery results in marked weight loss and may lead to improved operations. The findings may also improve our understanding of the causes of obesity, which could lead to new less invasive treatments.